8-pyridazinylcarbamoyl ergolines

ABSTRACT

Ergoline derivatives of formula: ##STR1## wherein n=0,1,2; R 1  =H, CH 3  ; R 2  =H, CH 3 , halogen; R 3  =H, OCH 3  ; R 4  =hydrocarbon group and R 5  is a residue of general formula II, III, IV, V, VI, VII: ##STR2## wherein R 6  =H, Cl, OCH 3 , NR 11  R 12 , wherein R 11  and R 12  =H, lower alkyl; phenyl or are bonded together to form a heterocyclic ring, R 7 , R 8  and R 9  and R 10  =H or C 1  -C 3  alkyl, with the proviso that if R 5  is of formula II and R 2  =R 7  =R 8  =H, then R 4  is not methyl or n is not 0. 
     Pharmaceutically acceptable acid addition salts are also provided. A method for their preparation is also provided. 
     The compounds have anti-depressive, anti-hypertensive and antiprolactin activity.

This application is a continuation of application Ser. No. 578,306,filed Feb. 9, 1984, now abandoned, which is a continuation of Ser. No.398,894, filed 7/16/1982, now abandoned.

This invention relates to ergoline derivatives, to processes for theirpreparation, and to pharmaceutical compositions containing them.

More particularly, this invention relates to ergoline derivatives havingthe general formula I: ##STR3## wherein n is 0, 1 or 2, R₁ represents ahydrogen atom or a methyl group, R₂ represents a hydrogen or halogenatom or a methyl group, R₃ represents a hydrogen atom or a methoxygroup, R₄ represents a hydrocarbon group having from 1 to 4 carbonatoms, and R₅ is a residue of the general formula II, III, IV, V, VI,VII or VIII: ##STR4## wherein R₆ represents a hydrogen or chlorine atomor a methoxy group, and each of R₇, R₈ and R₉ independently represents ahydrogen atom or an alkyl group having from 1 to 3 carbon atoms, withthe proviso that if R₅ represents a residue of the general formula IIand R₂, R₇ and R₈ all represent hydrogen atoms then either R₄ does notrepresent a methyl group or n is not 0, or the substituent on C₈ is notin β configuration, R₁₀ represents a hydrogen atom or an alkyl grouphaving from 1 to 3 carbon atoms, and either each of R₁₁ and R₁₂independently represents a hydrogen atom, a C₁ to C₄ alkyl group or aphenyl group, or R₁₁ and R₁₂ together with the nitrogen atom to whichthey are bonded form a heterocyclic ring, and further providespharmaceutically acceptable salts of such ergoline derivatives.

Although in the general formula thr term "halogen" should be construedas preferably encompassing chlorine and bromine atom, nevertheless, theterm "halogen" also encompasses the fluorine atom.

In the definition of R₄, a hydrocarbon group having from 1 to 4 carbonatoms is intended to include alkyl, cycloalkyl and unsaturated (bothethylenically and acetylenically) groups.

Representative groups include methyl, ethyl, n-propyl, isopropyl, butyl,t-butyl, isobutyl, methylcyclopropyl, allyl and propargyl.

When R₁₁ and R₁₂ together with the nitrogen atom to which they arebonded form a heterocyclic ring, this ring is preferably selected fromthe group consisting of pyrrolidine, piperidino, morpholino, pyrazole,imidazole and pyrrole.

The ergoline derivatives according to the invention may be prepared bythe high-yield mixed anhydride method using the relatively stable andreadily accessible mixed anhydride of the appropriate 8-carboxy-ergolineIX: ##STR5## wherein n, R₁, R₂, R₃ and R₄ have the above meanings, withethoxyformic acid.

The mixed ethoxyformic anhydride can be prepared by reacting theergoline IX with ethyl chloroformate in a solvent such astetrahydrofuran, dimethylformamide, or dioxan at 0° C. for 5-6 hours inthe presence of an organic base such as triethylamine.

The so-obtained mixed anhydride may be converted into an ergolinederivative of the general formula I by reacting it with an amine R₅ --H,wherein R₅ has the above meaning, at room temperature for a period of2-24 hours. This process is also considered to be within the scope ofthe invention.

The crude product may be purified by crystallization, salt formation, orby chromatography on a column of neutral aluminum oxide.

The ergoline-8-carboxylic acids IX are known compounds or may beprepared by established procedures.

The ergoline derivatives according to the present invention and theirpharmaceutically acceptable salts are useful antidepressant agents andthey also display from moderate to good antiprolactinic activity andfrom moderate to good antihypertensive activity.

Accordingly, this invention also provides a pharmaceutical compositioncomprising an ergoline derivative having the general formula I or apharmaceutically acceptable salt thereof in admixture with apharmaceutically acceptable diluent or carrier.

The antidepressant activity of the ergoline derivatives according to theinvention can be evaluated by antagonism to reserpine-inducedblepharospasm and hypothermia.

As a compound disclosed in Belgian Patent No. 841,049 has a structuralformula similar to that shown herein, applicants have ascertained byapplicants' test that it prevents reserpine-induced blepharospasm andhypothermia with ED₅₀ 's of 7 and 15 mg/kg p.o. Said compound is1,6-dimethyl-8β-(2-thiazolyl-carbamoyl)-ergoline, and this was used as areference standard drug, besides the tricyclic antidepressantimipramine, for the compounds of the present invention.

It has now been found that the products according to the presentinvention have a surprisingly higher activity as compared with the priorart compounds referred to above in preventing reserpine-induced symptomswith ED₅₀ falling in a dose range of from 0.2 to 5 mg/kg p.o., and withvery low orientative acute toxicities. This is shown in the followingtable:

    ______________________________________                                                 Reserpine antagonism                                                                             Orientative acute                                 Product of                                                                             (ED.sub.50, mg/kg p.o.)                                                                          toxicity (LD.sub.50,                              Example  Blepharospasm                                                                             hypothermia                                                                              mg/kg, p.o.)                                  ______________________________________                                        7        0.5         0.6        >300                                          6        2.5         4.0        >300                                          4        0.2         0.6        >300                                          16       1.0         1.7        >800                                          5        3.6         4.5        >600                                          10       3.5         3.1        >600                                          Imipramine                                                                             8.1         18.2       200-400                                       ______________________________________                                    

The tests were performed in an air-conditioned room at a constanttermperature of 19°±1° C. Randomized groups of male mice wererespectively treated by gavage with appropriate screening doses (from amaximum of 25 mg/kg below) of the test compounds, suspended in thevehicle (Methocel 0.5%; 1 ml/100 g b.w.), or with the vehicle alone. Onehour later the animals received an i.p. injection of reserpine (1.5mg/kg; 1 ml/100 g b.w.), and one of the control groups the same volumeof the vehicle alone (blank controls).

Three hours after pretreatments, i.e. two hours after reserpine orvehicle treatments, blepharospasm was evaluated in scores as proposed byRubin et al. (J. Pharmacol. 120, 125 (1957)). Two hours after the abovementioned evaluation the rectal temperature of the animals was recordedby an appropriate probe connected to a digital thermometer (Ellab DU-3).

The following examples still further illustrate the invention.

EXAMPLE 1 6-methyl-8β-(6-chloro-3-pyridazinyl-carbamoyl)-ergoline (I:R₁=R₂ =R₃ =H,R₄ =CH₃,R₅ =IV,R₆ =Cl)

A mixture of 15.02 g of 6-methyl-8β-carboxy-ergoline and 7 ml oftriethylamine in 400 ml of anhydrous tetrahydrofuran was warmed at 50°C. for 1 hour. To the cooled suspension 5.34 ml of ethyl chloroformatein 20 ml of tetrahydrofuran were added slowly and the stirring wascontinued for 6 hours at 0° C. After filtration the clear solutiontreated with 7.12 g of 3-amino-6-chloro-pyridazine and left overnight atroom temperature. The solution was concentrated under vacuum, dissolvedin chloroform, and washed with potassium carbonate solution and thenwith water. The residue of the organic layer was chromatographed througha short column of alumina using chloroform as the eluting solvent. Inthis way 15 g of the title compound, m.p. 252°-254° C., were obtained.

EXAMPLES 2 to 38

Operating as in Example 1, the compounds in Table 2 below were preparedfrom the following ergoline derivatives and amines:

    ______________________________________                                                              Examples                                                ______________________________________                                        Ergoline derivative                                                           6-methyl-8β-carboxy-ergoline                                                                     2, 10, 27, 28, 32                                     1,6-dimethyl-10-methoxy-8β-carboxy-ergoline                                                      3, 11                                                 2,6-dimethyl-8β-carboxy-ergoline                                                                 4, 9, 16                                              1,6-dimethyl-8β-carboxy-ergoline                                                                 12                                                    6-allyl-8β-carboxy-ergoline                                                                      5, 6, 14                                              6-propyl-8β-carboxy-ergoline                                                                     7, 13                                                 6-isopropyl-8β-carboxy-ergoline                                                                  8, 15                                                 6-methyl-8β-carboxymethyl-ergoline                                                               17, 19, 25, 29,                                                               33, 35-38                                             6-methyl-8β-(2-carboxyethyl)-ergoline                                                            18, 20, 26, 30,                                                               31, 34, 40 and 41                                     6-methyl-8α-carboxy-ergoline                                                                    21-23                                                 1-methyl-6-propyl-8β-carboxy-ergoline                                                            24                                                    2-bromo-6-methyl-8β-carboxymethyl-ergoline                                                       39                                                    Amine                                                                         3-amino-6-methoxy-pyridazine                                                                          2, 36, 41                                             3-amino-6-chloro-pyridazine                                                                           3-5, 19, 20,                                                                  23, 39                                                2-amino-thiazole        6-9, 17, 18,                                                                  22, 24                                                2-amino-5-methyl-1,3,4-thiadiazole                                                                    10-16, 21, 25, 26                                     5-amino-3-methyl-isothiazole                                                                          27, 29, 30                                            3-amino-isothiazole     28, 31                                                3-methyl-5-amino-1,2,4-thiadiazole                                                                    32-34                                                 3-aminopyridazine       35, 40                                                3-amino-6-(1-pyrrolidinyl)-pyridazine                                                                 37                                                    3-amino-6-(1-pyrrolyl)-pyridazine                                                                     38                                                    ______________________________________                                    

    __________________________________________________________________________    Ex-                                                                           am-                          General Formula I        m.p. yield              ple                                                                              Product                   n R.sub.1                                                                          R.sub.2                                                                          R.sub.3                                                                           R.sub.4                                                                           R.sub.5  (°C.)                                                                       (%)                __________________________________________________________________________     2 6-methyl-8β-(6-methoxy-3-pyridazinyl-                                                              0 H  H  H   CH.sub.3                                                                          IV, R.sub.6 = CH.sub.3                                                                 273-274                                                                            65                    carbamoyl)-ergoline                                                         3 1,6-dimethyl-10-methoxy-8β-(6-chloro-3-                                                            0 CH.sub.3                                                                         H  CH.sub.3 O                                                                        CH.sub.3                                                                          IV, R.sub.6                                                                            140-142                                                                            70                    pyridazinyl-carbamoyl)-ergoline                                             4 2,6-dimethyl-8β-(6-chloro-3-pyridazinyl-                                                           0 H  CH.sub.3                                                                         H   CH.sub.3                                                                          IV, R.sub.6                                                                            278-280                                                                            75                    carbamoyl)-ergoline                                                         5 6-allyl-8β-(6-chloro-3-pyridazinyl-                                                                0 H  H  H   allyl                                                                             IV, R.sub.6                                                                            230-232                                                                            65                    carbamoyl)-ergoline                                                         6 6-allyl-8β-(2-thiazolyl-carbamoyl)-ergoline                                                        0 H  H  H   allyl                                                                             II, R.sub.7 = R.sub.8 =                                                                170-172                                                                            70                  7 6-propyl-8β-(2-thiazolyl-carbamoyl)-ergoline                                                       0 H  H  H    -n-C.sub.3 H.sub.7                                                               II, R.sub.7 = R.sub.8 =                                                                200-202                                                                            64                  8 6-isopropyl-8β-(2-thiazolyl-carbamoyl)-ergoline                                                    0 H  H  H    .sub.-i-C.sub.3 H.sub.7                                                          II, R.sub.7 = R.sub.8 =                                                                252-254                                                                            55                  9 2,6-dimethyl-8β-(2-thiazolyl-carbamoyl)-ergoline                                                   0 H  CH.sub.3                                                                         H   CH.sub.3                                                                          II, R.sub.7 = R.sub.8 =                                                                187-189                                                                            72                 10 6-methyl-8β-[2-(5-methyl-1,3,4-thiadiazolyl)-                                                      0 H  H  H   CH.sub.3                                                                          III, R.sub.9                                                                           263-265b.3                                                                         71                    carbamoyl]-ergoline                                                        11 1,6-dimethyl-10-methoxy-8β-[2-(5-methyl-1,3,4-                                                     0 CH.sub.3                                                                         H  CH.sub.3 O                                                                        CH.sub.3                                                                          III, R.sub.9                                                                           218-220b.3                                                                         68                    thiadiazolyl)-carbamoyl]-ergoline                                          12 1,6-dimethyl-8β-[2-(5-methyl-1,3,4-thiadiazolyl)-                                                  0 CH.sub.3                                                                         H  H   CH.sub.3                                                                          III, R.sub.9                                                                           152-154b.3                                                                         80                    carbamoyl]-ergoline                                                        13 6-propyl-8β-[2-(5-methyl-1,3,4-thiadiazolyl)-                                                      0 H  H  H    -n-C.sub.3 H.sub.7                                                               III, R.sub.9                                                                           202-204b.3                                                                         70                    carbamoyl]-ergoline                                                        14 6-allyl-8β-[2-(5-methyl-1,3,4-thiadiazolyl)-                                                       0 H  H  H   allyl                                                                             III, R.sub.9                                                                           156-158b.3                                                                         67                    carbamoyl]-ergoline                                                        15 6-isopropyl-8β-[2-(5-methyl-1,3,4-thiadiazolyl)-                                                   0 H  H  H    .sub.-i-C.sub.3 H.sub.7                                                          III,R.sub.9                                                                            194-196b.3                                                                         73                    carbamoyl]-ergoline                                                        16 2,6-dimethyl-8β-[2-(5-methyl-1,3,4-thiadiazolyl)-                                                  0 H  CH.sub.3                                                                         H   CH.sub. 3                                                                         III, R.sub.9                                                                           258-260b.3                                                                         70                    carbamoyl]-ergoline                                                        17 6-methyl-8β-(2-thiazolyl-carbamoylmethyl)-ergoline                                                 1 H  H  H   CH.sub.3                                                                          II, R.sub.7 = R.sub.8 =                                                                285-287                                                                            70                 18 6-methyl-8β-[2-(2-thiazolyl-carbamoyl)-ethyl]-ergoline                                             2 H  H  H   CH.sub.3                                                                          II, R.sub.7 = R.sub.8 =                                                                246-248                                                                            72                 19 6-methyl-8β-(6-chloro-3-pyridazinyl-carbamoylmethyl)-                                              1 H  H  H   CH.sub.3                                                                          IV, R.sub.6                                                                            285-287                                                                            68                    ergoline                                                                   20 6-methyl-8β-[2-(6-chloro-3-pyridazinyl-carbamoyl)-                                                 2 H  H  H   CH.sub.3                                                                          IV, R.sub.6                                                                            280-282                                                                            71                    ethyl]-ergoline                                                            21 6-methyl-8β-[2-(5-methyl-1,3,4-thiadiazolyl)carbamoyl]-                                            0 H  H  H   CH.sub.3                                                                          III, R.sub.9                                                                           293-5sub.3                                                                         69                    ergoline                                                                   22 6-methyl-8β-(2-thiazolyl-carbamoyl)ergoline                                                        0 H  H  H   CH.sub.3                                                                          II, R.sub.7 = R.sub.8 =                                                                253-4                                                                              72                 23 6-methyl-8β-(6-chloro-3-pyridazinyl-carbamoyl)ergoline                                             0 H  H  H   CH.sub.3                                                                          IV, R.sub.6                                                                            300l 58                 24 1-methyl-6-propyl-8β-(2-thiazolyl-carbamoyl)-ergoline                                              0 CH.sub.3                                                                         H  H    -n-C.sub.3 H.sub.7                                                               II, R.sub.7 = R.sub.8  =                                                               168-170                                                                            75                 25 6-methyl-8β-[2-(5-methyl-1,3,4-thiadiazolyl)-                                                      1 H  H  H   CH.sub.3                                                                          III, R.sub.9                                                                           300H.sub.3                                                                         68                    carbamoylmethyl]-ergoline                                                  26 6-methyl-8β-{2[2-(5-methyl-1,3,4-thiadiazolyl)-                                                    2 H  H  H   CH.sub.3                                                                          III, R.sub.9                                                                           275-277b.3                                                                         71                    carbamoyl]-ethyl}-ergoline                                                 27 6-methyl-8β-(3-methyl-5-isothiazolyl-carbamoyl)-                                                   0 H  H  H   CH.sub.3                                                                          V, R.sub.10                                                                            174-175b.3                                                                         62                    ergoline                                                                   28 6-methyl-8β-(3-isothiazolyl-carbamoyl)-ergoline                                                    0 H  H  H   CH.sub.3                                                                          VI       138-140                                                                            62                 29 6-methyl-8β-(3-methyl-5-isothiazolyl-carbamoylmethyl)-                                             1 H  H  H   CH.sub.3                                                                          V, R.sub.10                                                                            138-140b.3                                                                         65                    ergoline                                                                   30 6-methyl-8β-[2-(3-methyl-5-isothiazolyl-carbamoyl)-                                                2 H  H  H   CH.sub.3                                                                          V, R.sub.10                                                                            191-192b.3                                                                         55                    ethyl]-ergoline                                                            31 6-methyl-8β-[2-(3-isothiazolyl-carbamoyl)-ethyl]-                                                  2 H  H  H   CH.sub.3                                                                          VI       202-204                                                                            64                    ergoline                                                                   32 6-methyl-8β-[5-(3-methyl-1,2,4-thiadiazolyl)-carbamoyl]-                                           0 H  H  H   CH.sub.3                                                                          VII, R.sub.10                                                                          181-182b.3                                                                         68                    ergoline                                                                   33 6-methyl-8β-[5-(3-methyl-1,2,4-thiadiazolyl)-                                                      1 H  H  H   CH.sub.3                                                                          VII, R.sub.10                                                                          243-245b.3                                                                         60                    carbamoylmethyl] -ergoline                                                 34 6-methyl-8β-{2-[5-(3-methyl-1,2,4-thiadiazolyl)-                                                   2 H  H  H   CH.sub.3                                                                          VII, R.sub.10                                                                          145-147b.3                                                                         65                    carbamoyl]-ethyl}-ergoline                                                 35 6-methyl-8β-(3-pyridazinyl-carbamoylmethyl)-ergoline                                               1 H  H  H   CH.sub.3                                                                          IV, R.sub.6                                                                            230-232                                                                            61                 36 6-methyl-8β-(6-methoxy-3-pyridazinyl-                                                              1 H  H  H   CH.sub.3                                                                          IV, R.sub.6                                                                            258-260ub.3                                                                        71                    carbamoylmethyl)-ergoline                                                  37 6-methyl-8β-(6-pyrrolidinyl-3-pyridazinyl-                                                         1 H  H  H   CH.sub.3                                                                          VIII, R.sub.11                                                                         263-5                                                                              67                    carbamoylmethyl)-ergoline                                                                                                ##STR6##                        38 6-methyl-8β-[6-(pyrrolyl)-3-pyridazinyl-                                                           1 H  H  H   CH.sub.3                                                                          VIII, R.sub.11                                                                         241-243                                                                            70                    carbamoylmethyl]-ergoline                                                                                                ##STR7##                        39 2-bromo-6-methyl-8β-[(6-chloro-3                                                                   1 H  Br H   CH.sub.3                                                                          IV, R.sub.6                                                                            254-6                                                                              65                    pyridazinyl)carbamoylmethyl]-ergoline                                      40 6-methyl-8β-[2(3-pyridazinyl-carbamoyl)ethyl]-ergoline                                             2 H  H  H   CH.sub.3                                                                          IV, R.sub.6                                                                            233-5                                                                              75                 41 6-methyl-8β-[2(6-methoxy-3-pyridazinyl-                                                            2 H  H  H   CH.sub.3                                                                          IV, R.sub.6                                                                            268-270ub.3                                                                        69                    carbamoyl)ethyl]ergoline                                                   __________________________________________________________________________

What is claimed is:
 1. A compound which is6-methyl-8β-(6-chloro-3-pyridazinyl-carbamoyl)-ergoline.
 2. A compoundwhich is 2,6-dimethyl-8β-(6-chloro-3-pyridazinyl-carbamoyl)-ergoline. 3.A compound which is6-allyl-8β-(6-chloro-3-pyridazinyl-carbamoyl)-ergoline.